Journal
CELL CALCIUM
Volume 49, Issue 4, Pages 272-278Publisher
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.ceca.2011.03.002
Keywords
Nicotinic acetylcholine receptor; Slow channel congenital myasthenic syndrome; Calcium permeability; Fractional calcium current; Excitotoxicity
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Funding
- AFM (Association Francaise contre les Myopathies)
- Italian Ministry of Health
- Sapienza University, Rome
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In slow-channel congenital myasthenic syndrome, point mutations of the endplate acetylcholine receptor (AChR) prolong channel openings, leading to excessive Ca2+ entry with ensuing endplate degeneration and myasthenic symptoms. The Ca2+ permeability of the human endplate AChR-channel is quite high, and is further increased by two slow-channel mutations in its epsilon subunit, worsening the pathological cascade. To gain further support to the hypothesis that the e subunit plays a crucial role in controlling Ca2+ permeability of endplate AChR-channel, in this work we measured the fractional Ca2+ current (P-f, i.e., the percentage of the total current carried by Ca2+ ions) of a panel of AChR carrying slow-channel mutations in the alpha, beta and epsilon subunits detected in patients (alpha(N217K), alpha(S226Y), alpha(C418W). beta(V266A). beta(V266M), epsilon(1257F), epsilon(V265A) and epsilon(L269E)). We confirm that only mutations in the epsilon subunit altered Ca2+ permeability of AChR-channels, with epsilon(L269F) increasing P-f(10% vs. 7% of wild type AChR) and epsilon(1257F) decreasing it (to 4.6%). We also found that, for epsilon(L269F)-AChR, the Ca2+ permeability and ACh-induced cell death can be normalized by clinically relevant concentrations of salbutamol or verapamil, providing the first evidence that the Ca2+ permeability of AChR-channels can be modulated and this treatment may provide protection against excitotoxic insults. (C) 2011 Elsevier Ltd. All rights reserved.
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